Fas or ceramide induce apoptosis by Ras-regulated phosphoinositide-3-kinase activation.
We demonstrate a rapid and transient activation of phosphoinositide-3-kinase (PI-3-K) by Fas receptor triggering or cellular treatment with synthetic C6-ceramide. The stimulation of PI-3-K is critical for Fas or C6-ceramide-induced programmed cell death because transfection with a transdominant inhibitory PI-3-K construct or pre-treatment with the PI-3-K inhibitor wortmannin almost completely prevented Fas or C6-ceramide-mediated apoptosis. Treatment with the caspase inhibitor Ac-YVAD-cmk or cellular transfection with transdominant inhibitory N17Ras prevented PI-3-K stimulation by Fas, suggesting that Fas activates PI-3-K via caspases and Ras. N17Ras expression also prevented C6-ceramide-initiated PI-3-K stimulation. The notion of a PI-3-K regulation by Ras upon Fas receptor ligation or ceramide treatment is supported by co-immunoprecipitation experiments revealing an activation-dependent association of PI-3-K and Ras.
Gulbins
E
E
Department of Physiology, University of Tuebingen, Germany.
Brenner
B
B
Koppenhoefer
U
U
Linderkamp
O
O
Lang
F
F
D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002518:Ceramides / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D015398:Signal Transduction; D000077191:Wortmannin; D019014:fas Receptor / Q000502:physiology*
D000730:Androstadienes; D002518:Ceramides; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras); D000077191:Wortmannin; D019014:fas Receptor; C501009:HRAS protein, human